WU polyomavirus (WUV) is a newly discovered virus that has been widely detected in respiratory secretions of many patients suffering acute respiratory disease. Seroepidemiologic studies have determined that ~90% of adults in the general population have anti-WUV antibodies and thus the vast majority of the world's population has been infected at some point in time by WUV. Currently, the pathogenic potential of WUV is undefined. In some patients with acute respiratory disease, WUV is the only virus detected despite extensive screening for other respiratory viruses, raising the possibility that WUV causes respiratory disease. Based on paradigms provided by the known human pathogens BK and JC polyomaviruses, infection by WUV may result in persistent, lifelong infection that may lead to significant human disease in immunocompromised individuals. In addition, there has long been controversy as to whether SV40, BK and JC viruses play a role in human cancers; the recent discovery of Merkel polyomavirus and its strong association with Merkel cell carcinoma has provided the most compelling link to date between a polyomavirus and cancer. These studies raise the question of whether WUV might be associated with any tumors. Efforts to address these questions, as well as studies aimed at characterizing the fundamental virologic properties of WUV, would be greatly facilitated by the development of a cell culture replication system for WUV. The lack of any culture system for propagation of WUV is currently the fundamental barrier to further characterization of the virus and assessment of its relationship to human disease. For example, fulfillment of Koch's postulates, the gold standard for establishing microbial disease causality, necessarily requires that the agent be grown in culture. In addition, studies of receptors for WUV entry (and thus virus tropism), viral replication mechanisms and detailed analysis of intracellular WUV-host interactions are dependent on having robust culture systems. Successful culture of WUV is a critical milestone that would facilitate many future, long-term experiments essential for understanding of WUV biology.